Cholesterol: Wrong Target for Primary Prevention of Cardiovascular Disease?

Mark Hyman, MD
November 19, 2009

We have all been led to believe that cholesterol is bad and that lowering it is good.
Extensive pharmaceutical marketing of statins to both doctors and patients lead us to believe
that their benefit is proven to lower the risk of heart attacks and death.

But on what scientific evidence is this based, was does that evidence really show?

Roger Williams once said something that is very applicable to how we commonly view the
benefits of statins. There are liars, damn liars and statisticians.

We see prominent advertisements on television and in medical journals that statins therapy
results in a 36% reduction in the risk for a heart attack. What does that REALLY mean and what
how does it affect decisions about who should really be using these medication?

Consider the following:

If you lower LDL-C but have a low HDL there is no benefit to statins.i
If you lower LDL-C but dont reduce inflammation (C-reactive protein), there is no
benefit to statins.ii
If you are a healthy woman with high cholesterol, there is no proof that taking statins
reduces your risk of heart attack or death.iii
If you are a man or a woman over 69 years old with high cholesterol, there is no proof
that taking statins reduces your risk of heart attack or death.iv
ENHANCE: Aggressive cholesterol treatment with two medications (Zocor and Zetia)
lowered cholesterol much more than one drug alone, but led to more plaque build up in
the arteries and no fewer cardiac events.v
50-75% of people who have heart attacks have normal cholesterol.vi
Older patients with lower cholesterol have higher risks of death than those with higher
cholesterol.vii
Countries with higher average cholesterol than Americans such as the Swiss or Spanish
have less heart disease.
JUPITER: Recent evidence shows that it is likely statins ability to lower inflammation that
accounts for the benefits of statins, not their ability to lower cholesterol.viii

So whom do the statin drugs work for anyway? They work for secondary prevention in those
who have had cardiac events to prevent further cardiac events or death. The evidence is clear
for secondary prevention. And they have minimal benefit for primary prevention for middle-
aged men who have multiple risk factors for heart disease such as high blood pressure, obesity,
or diabetes. However for all other groups of people, statins do not provide a net benefit for
primary prevention when the data for primary and secondary prevention are carefully
separated.

So why did the 2004 National Cholesterol Education Program guidelines expand the previous
guidelines to recommend that more people take statins (from 13 million to 40 million) and
promote statins for primary prevention (or about 75% of the patients taking statins)? Could it
have been that 8 of the 9 experts on the panel who developed these guidelines had financial
ties to the drug industry? Thirty-four other non-industry affiliated experts sent a petition to
protest the recommendations to the National Institutes of Health saying the evidence was
weak. It was like having a fox guard the chicken coop.

Its all in the spin. The spin of the statistics and numbers. And its easy to get confused.

When you look under the hood of the research data you find that the touted 36% reduction
means a reduction of the number of people getting heart attacks or death from 3% to 2% (or
about 30-40%). It means that only 1 out of 100 people treated will receive a benefit.

And that data also show that treatment with statins only is effective for secondary prevention,
in other words for those with documented coronary events. In those who DONT have
documented heart disease, there is no benefit when the primary and secondary prevention
data are teased out from the large trials.

In those at high risk for heart disease about 50-100 people would need to be treated for 5 years
to reduce one cardiovascular event. Just to put it in perspective if a drug works, it has a very
low NTT (number needed to treat). For example, if you have a urine infection and take an
antibiotic, you will get near a 100% benefit. The number needed to treat is 1. So if you have
an NTT of 50-100 like statins do for preventing heart disease in 75% of the people who take
them, it is basically a crap shoot.6

Yet at a cost of over $28 billion a year, 75% of all statin prescriptions are for exactly this type of
unproven primary prevention. Simply applying the science over 10 years would save over $200
billion. This is just one example of reimbursed but unproven care. We need not only prevent
disease but also prevent the wrong type of care.

It these medications were without side effects, then you may be able to justify the risk but
they cause myopathy (even in the absence of pain and elevated CPK), sexual dysfunction, liver
and nerve damage and other problems in 10-15% of patients who take them.ix

If lowering cholesterol is not the great panacea that we thought, how do we prevent and treat
heart disease.

If lipids are implicated in the development of atherosclerosis, then is the right question how
low is the LDL target level? Could it be that the right question is what causes lipids to become
atherogenic and how do we treat that? Conventional methods of lipid analysis are outdated
because we now understand that atherogenic particles are small dense HDL and LDL and large
VLDL particles.x Insulin resistance, oxidative stress and inflammation cause this atherogenic
lipid phenotype, and while statins may lower inflammation marginally, they do not have
significant effect on increasing lipid particle size.

It is lifestyle changes including a low glycemic load diet and exercise that lowers atherogenic
lipid particles, oxidative stress and inflammation. Niacin also can increase lipid particle size and
raise HDL-C and reverse atherosclerotic plaque.xi We use the tools we have, not necessarily
the right medicine for the problem. The right medicine for heart disease is a healthy
lifestyle, which works better than medication. Statin use is not without risk and the benefit is
overstated, especially for it major indication primary prevention. The question then
becomes, what are the true contributors to cardiovascular disease?

Prime Contributors to Cardiovascular Disease

The interaction of genes, lifestyle, and environment determines risk. These dynamic
interactions lead to the primary drivers of cardiovascular disease including insulin resistance,
inflammation, oxidative stress and inflammation,xii environmental toxins, xiii and stress.

The data show that preventing heart disease has very little to do with simply lowering LDL
cholesterol with statins. Our current thinking about how to treat and prevent heart disease is
at best misguided, and at worst harmful. We believe we are treating the causes of heart
disease by lowering cholesterol, lowering blood pressure, lowering blood sugar with
medication. But we are treating surrogate risk factors, not causes. The real question is what
causes high cholesterol, high blood pressure and elevated glucose in the first place.xiv It is
certainly not a medication deficiency!

It is the environment influencing gene expression that determines risk. In other words, it is the
way we eat, how much we exercise, how we deal with stress and the effects of environmental
toxins that are the underlying causes of high cholesterol, high blood pressure and high blood
sugar. That is what determines the risk of heart disease, not a lack of medication.

The research clearly shows that changing how we live is a much more powerful intervention for
preventing heart disease than any medication. The EPIC study published in the Archives of
Internal Medicine studied 23,000 peoples adherence to 4 simple behaviors (not smoking,
exercising 3.5 hours a week, eating a healthy diet [fruits, vegetables, beans, whole grains, nuts,
seeds, and limited amounts of meat], and maintaining a healthy weight [BMI <30]). In those
adhering to these behaviors, 93% of diabetes, 81% of heart attacks, 50% of strokes, and 36% of
all cancers were prevented.xv

And the INTERHEART study, published in The Lancet in 2004, followed 30 000 people and found
that changing lifestyle could prevent at least 90% of all heart disease.xvi
These studies are among a large evidence base documenting how lifestyle intervention is often
more effective in reducing cardiovascular disease, hypertension, heart failure, stroke, cancer,
diabetes, and deaths from all causes than almost any other medical intervention.xvii It is
because lifestyle doesnt only reduce risk factors such as high blood pressure, blood sugar, or
cholesterol. Our lifestyle and environment influence the fundamental causes and biological
mechanisms leading to disease: changes in gene expression, which modulate inflammation,
oxidative stress, and metabolic dysfunction. Those are the real reasons for cardiovascular
disease, not a statin deficiency.

Ignoring or giving lip service to the underlying causes and treating only risk factors is somewhat
like mopping up the floor around an overflowing sink instead of turning off the faucet, which is
why medications usually have to be taken for a lifetime. When the underlying lifestyle causes
are addressed, patients often are able to stop taking medication and avoid surgery.

Cholesterol is only one of many factors that lead to cardiovascular disease, and it may not even
be the most important one. Inflammation and insulin resistance are much more important and
these are driven by what we eat, now much we exercise, how we deal with stress and our body
burden of environmental toxins. We focus on cholesterol because it is the factor for which we
have best medication. But remember if all you have is a hammer, then everything looks like a
nail.

A comprehensive approach to treating the system, not the symptom using diet changes, based
on a whole food, plant based diet rich in omega 3 fats, antioxidants and phytonutrients,
supplements, exercise, and strategies for treating chronic low level environmental toxicity can
have a dramatic impact the risk of heart disease. And there is a good side effect--this approach
reduces the risk of nearly all chronic diseases.

i
Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New
Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med.
2007 Sep 27;357(13):1301-10.
ii
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ,
MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent
vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207.
iii
Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet. 2007 Jan 20;369(9557):168-9
iv
IBID
v
Brown BG, Taylor AJ Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? Engl J Med 358:1504,
April 3, 2008 Editorial
vi
Hansson GK Inflammation, Atherosclerosis, and Coronary Artery Disease N Engl J Med 352:1685, April 21, 2005
viivii
Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people
from the Honolulu Heart Program: a cohort study. Lancet. 2001 Aug 4;358(9279):351-5.
viii
Mora S, Ridker PM. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER)--can C-reactive protein be used to target statin therapy in primary prevention? Am J
Cardiol. 2006 Jan 16;97(2A):33A-41A.
ix
Kuncl RW. Agents and mechanisms of toxic myopathy. Curr Opin Neurol. 2009 Oct;22(5):506-15. PubMed PMID:
19680127.
x
Decewicz DJ, Neatrour DM, Burke A, Haberkorn MJ, Patney HL, Vernalis MN, Ellsworth DL. Effects of
cardiovascular lifestyle change on lipoprotein subclass profiles defined by nuclear magnetic resonance
spectroscopy. Lipids Health Dis. 2009 Jun 29;8:26.
xi
Cziraky MJ, Watson KE, Talbert RL. Targeting low HDL-cholesterol to decrease residual cardiovascular risk in the
managed care setting.J Manag Care Pharm. 2008 Oct;14(8 Suppl):S3-28
xii
Hansson GK. Atherosclerosis--an immune disease: The Anitschkov Lecture 2007. Atherosclerosis. 2009
Jan;202(1):2-10.
xiiixiii
Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E. Blood lead below 0.48 micromol/L (10 microg/dL)
and mortality among US adults. Circulation. 2006 Sep 26;114(13):1388-94.
xiv
Mozaffarian D, Wilson PW, Kannel WB. Beyond established and novel risk factors: lifestyle risk factors for
cardiovascular disease. Circulation. 2008;117(23):3031-3038
xv
Ford ES, Bergmann MM, Krger J, Schienkiewitz A, Weikert C, Boeing H.
Healthy living is the best revenge: findings from the European Prospective Investigation Into Cancer and Nutrition-
Potsdam study. Arch Intern Med. 2009 Aug 10;169(15):1355-1362.
xvi
Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study Investigators.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART
study): case-control study. Lancet. 2004;364(9438):937-952
xvii
American College of Preventive Medicine. Lifestyle MedicineEvidence Review. June 30, 2009. Available at:
http://www.acpm.org/LifestyleMedicine.htm. Accessed September 18, 2009.